The candidate for this NCI Transition Career Development Award (K22) is Michael Lazarus, Ph.D., a postdoctoral researcher in the lab of Professor Kevan Shokat at the University of California, San Francisco. Dr. Lazarus has a strong background in structural biology and biochemistry from his Ph.D. but has sought to gain additional experience in proteomics, cell biology, and ribosomal profiling in his postdoctoral and K22 award period. At the end of the award period, Dr. Lazarus will have a well-rounded and exciting set of skills with which he will be able to carry out cutting edge research in cancer biology related to nutrient signaling. His long-term goal is to have his own lab at a research university focused on studying the mechanisms by which cells respond to nutrient changes, how these mechanisms can be altered in cancer, and finally how they can be exploited for novel therapeutic strategies. The focus of this research proposal centers around two unusual enzymes that regulate cellular responses to starvation. One is a protein called elongation factor-2 kinase (eEF2K) which functions to regulate translation in cells in response to nutrient deprivation. The kinase belongs to an atypical family of kinases called alpha kinases; it has a non-canonical sequence and has not benefitted from the recent development of tools used to study conventional protein kinases. eEF2K has been shown to be important for tumor survival by rendering cancer cells resistant to nutrient changes, but the mechanisms by which it does this are unclear. In this proposal, Dr. Lazarus seeks to identify novel substrates of eEF2K and understand how regulation of translation allows cancer cells to adapt to nutrient deprivation. By determining which transcripts are most affected by eEF2K activity, a new understanding of translation regulation will emerge. The other enzyme is a kinase called ULK1 that initiates autophagy in cells, a process whereby cells can degrade cellular components for energy when nutrients are low. Dr. Lazarus will develop the first cellular inhibitors of ULK1 and probe the kinase's function in cancer. By developing tools to study these two enzymes, Dr. Lazarus will have a solid program in studying nutrient signaling in cancer. Dr. Lazarus has assembled an impressive team of scientists to help him tackle these challenging questions and learn new skills to complete his training and transition into an independent investigator. His current mentor is Kevan Shokat, a world leader in indentifying substrates of kinases, developing selective kinase inhibitors, and using chemical tools to unravel complex signaling pathways in cancer. Dr. Lazarus has been working in Professor Shokat's laboratory, and will develop tools to understand eEF2K and ULK1. In Professor Shokat's lab, Michael has been learning techniques of substrate identification as well as organic synthesis for making new inhibitors. In addition, Dr Lazarus has been receiving training from two leading scientists who are longtime collaborators with Professor Shokat at UCSF. Professor William Weiss is a world expert on neuroblastoma models and will train Dr. Lazarus to investigate the role of eEF2K in cancer cell lines where the kinase has been strongly linked to patient prognosis. By learning how to investigate the kinase and its substrates in relevant cell lines, Dr. Lazarus is gaining experience in fundamental cell biology techniques as well as learning new avenues of eEF2K function in relevant disease models that will become part of Dr. Lazarus's independent research. Dr. Lazarus is also benefiting from working with Professor Davide Ruggero, who is a leading expert on translation regulation and ribosomal profiling. By working with Professor Ruggero, Dr. Lazarus will learn techniques in ribosomal profiling and biochemical analysis of translation. Both Professor Weiss and Professor Ruggero are located at the UCSF campus and have been meeting frequently with Dr. Lazarus and Professor Shokat to provide guidance on this collaborative and multi-disciplinary project. Dr. Lazarus has been working closely with members of Professor Weiss's and Professor Ruggero's labs to learn new techniques and answer questions about his project. This rich environment at UCSF will be a key component of Dr. Lazarus's training as a scientist, since his mentor has ongoing collaborations with dozens of faculty members at UCSF with different expertises. These more informal interactions and advice will be an invaluable resource. In addition, Dr. Lazarus will attend key workshops UCSF that will supplement his laboratory training with professional development. In summary, because of this rigorous training plan and collaborative environment at UCSF, Dr. Lazarus will be uniquely positioned to make new discoveries about eEF2K and ULK1 and also be ready for a strong independent academic career.